A Likely Pathogenic variant in the Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6.

BACKGROUND

Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the gene, also called the Dutch founder variant.

OBJECTIVE

To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the gene.

RESULTS

We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with functional tests was observed. This was confirmed by functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier.

CONCLUSIONS

The c.1222C > A p.(Arg408Ser) variant in the gene is a likely pathogenic variant causing NEM6.